Not applicable.
This invention relates to new and useful fiber-forming biabsorbable polymeric materials, such as bioabsorbable triglycolic acid poly(ester-amides)s, derived from reacting diamidediols with a diacid chloride deriviative of 3,6-dioxaoctanedioic acid, also known as xe2x80x9ctriglycolic acidxe2x80x9d. This invention also relates to new and useful diol terminated poly(ester-amide)s of triglycolic acid made by the polymerization of diamine diols with triglycolic acid poly(ester-amides)s, and to products of reacting such diol terminated poly(ester-amide)s with cyclic monomers to produce block copolymers. This invention further relates to methods of making new and useful fiberous bioabsorbable implants, including surgical sutures and molded devices, of such block copolymers or other polymeric materials.
Since the first synthetic absorbable suture made from braided multifilaments of poly(glycolic acid) was introduced in about the year 1970, advancements in the design and synthesis of bioabsorbable polymers have resulted in continuous improvements in absorbable suture products.
In addition to the suture application, high strength, highly flexible, tough, and durable fibers that possess a prolonged flex fatigue life are needed for use as braided, knitted, woven, or non-woven implants to augment and temporarily reinforce autologous tissue grafts or preserve as scaffolds for tissue regeneration. One example of such an implant is known as a ligament augmentation device (LAD) used to reconstruct the anterior cruciate ligament (ACL) of the knee. Bioabsorbable fibers of the prior art, such as poly(L-lactic acid) (PLA), have not been successful in this application due to low flex fatigue life, shedding of wear debris due to the brittle nature of the fibers, and prolonged bioabsorption time.
Other well known uses for bioabsorbable polymers that have not been fully realized or perfected with available polymers of the prior art include scaffolds for tissue engineering, bioabsorbable knitted vascular grafts, drug-releasing devices, growth factor-releasing implants for bone and tissue regeneration, and fiber-reinforced composites for orthopedic applications. For example, composites of polymers reinforced with dissimilar materials, such as dissolvable glass fiber reinforced poly(lactic acid) are unacceptable for use as implants, the following reasons. Although dissolvable glass fibers provide high modulus needed for the composite to have high initial strength and stiffness, adhesion between glass and polymer invariably fails prematurely in vivo resulting in devices with unacceptable in vivo performance.
Self-reinforced composites were developed as an alternative to composites of polymers reinforced with dissimilar materials, such as those described above. In self-reinforced fiber composites both reinforcing fibers and matrix are made of the same material. Although the stiffness is lower than can be achieved with glass fibers, this alternative type of composite ensures good adhesion between fiber and matrix and thus offers the possibility of longer lasting in vivo strength. Self-reinforced poly(glycolic acid) (PGA) rods, pins and screws made by hot pressing or sintering PGA fibers have shown promise in clinical use. The main disadvantage of PGA in general is that it degrades too fast for orthopedic applications and releases an excessive concentration of acidic degradation products into the surrounding tissue.
Despite the advancements in the art of producing polymeric materials and methods for making polymeric materials suitable for use in sutures, molded devices, and similar surgical devices. Specifically, there continues to be a need for new fibers that are monofilament, has a high initial tensile knot strength, retain useful strength in vivo for about two weeks or longer, are fully bioabsorbed within a few months after strength loss, and have very low bending stiffness.
The present invention consists of a biabsorbable polymer of the general formula (I): 
wherein, x is from 2 to 10, m and n are independently from 0 to 2000, p is from 10 to 2000, and A is comprised of from 0 to 90 mole % A1 in combination with other structures selected from the group consisting of A2 and A3, wherein:
A1 is defined by the formula (II): xe2x80x94(CH2)yxe2x80x94, wherein y is from 2 to 10;
A2 is defined by the formula (III): 
wherein R1 is selected from the group consisting of:
i) a linear alkene having from 1 to 5 carbon atoms;
ii) an ester defined by the formula(IV): xe2x80x94(CH2)x1xe2x80x94Oxe2x80x94(CH2)y1xe2x80x94, wherein x1 (the end attached to the amide carbonyl) is from 1 to 4 and y1 (the end attached to the ester oxygen) is independently from 2 to 6; and
iii) a benzyl alkane of the formula(V): xe2x80x94(CH2)x2xe2x80x94C6H4xe2x80x94 wherein the xe2x80x94(CH2)x2 end of the benzyl alkane is covalently attached to the amide carbonyl of formula III, and x2 is from 0 to 1; and
iv) an alkyl benzyl ester of the formula(VI):
xe2x80x94(CH2)x3xe2x80x94C6H4xe2x80x94Oxe2x80x94(CH2)y3xe2x80x94,
wherein the xe2x80x94(CH2)x3 end of the alkyl benzyl ester is attached to the amide carbonyl of formula III, x3 is from 0 to 1, the (CH2)y3xe2x80x94 end of the alkyl benzyl ester is attached to the ester oxygen of formula I, and y3 is independently from 2 to 6; and
R2 is selected from the group consisting of linear alkylenes having from 2 to 10 carbon atoms; and
A3 is defined by the following structure: 
wherein R3 is a divalent aliphatic or aromatic hydrocarbon radical having from 3 to about 8 carbon atoms; and
E2 is defined by a formula selected from the group of formulae consisting of:
formula (V): [xe2x80x94COxe2x80x94CHR4xe2x80x94Oxe2x80x94], wherein R4 is selected from the group consisting of xe2x80x94H (from glycolide) and xe2x80x94CH3 (from lactide);
formula (VI): [xe2x80x94COxe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94];
formula (VII): [xe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94];
formula (VIII): [xe2x80x94COxe2x80x94(CH2)5xe2x80x94Oxe2x80x94]; and
combinations of formula V to VIII; and
E1 has the same structure as E2 except that the orientation of the formula of E1 is reversed.
In an alternative embodiment, the invention is the bioabsorbable polymer of general formula (I), above, wherein x is 2, and except as indicated all the other variables in the formula are defined as described above, except that:
A2 is defined by formula (III): 
wherein: R1 is selected from the group consisting of:
i) a linear alkene having from 1 to 5 carbon atoms;
ii) an ester defined by formula(IV): xe2x80x94(CH2)x1xe2x80x94Oxe2x80x94(CH2)y1xe2x80x94, wherein the xe2x80x94(CH2)x1 end of the ester is attached to the amide carbonyl of formula (III), x1 is from 1 to 4 and y1 is independently from 2 to 6;
iii) a benzyl alkane of formula(V): 
wherein the xe2x80x94(CH2)x2 end of the benzyl alkane is covalently attached to the amide carbonyl of formula III, and x2 is from 0 to 1; and
iv) an alkyl benzyl ether of formula(VI): 
wherein the xe2x80x94(CH2)x3 end of the alkyl benzyl ester is attached to the amide carbonyl of formula III, x3 is from 0 to 1, the (CH2)y3xe2x80x94 end of the alkyl benzyl ester is attached to the ester oxygen of formula I, and y3 is independently from 2 to 6; and
R2 is selected from the group consisting of linear alkyenes having from 4 to 1 0 carbon atoms.
The present invention also consists of bioabsorbable materials made from the bioabsorbable polymer of the invention designed for in vivo use or implantation, including but not limited to bioabsorbable sutures, and a self-reinforced device comprised of fused or sintered fibers of the bioabsorbable polymer. The present invention further consists of a method of making self-reinforced materials from the bioabsorbable polymer of this invention.
The diacidchloride derivative of 3,6-dioxaoctanedioic acid, commonly known as xe2x80x9ctriglycolyl chloridexe2x80x9d, has been discovered in the present invention to be an ideal monomer or comonomer for polymerization with diamidediols to produce poly(ester-amide)s capable of forming flexible, tenacious monofilament fibers with adequate bioabsorption time for use as surgical suture. Triglycolic acid is inexpensive and readily available since it can be economically produced by nitric acid oxidation of triethylene glycol. The conversion of triglycolic acid into triglycolyl chloride is described in U.S. Pat. No. 3,966,766, the teachings of which are incorporated herein (see Example 1, xe2x80x9cPreparation of triglycolyl chloridexe2x80x9d).
Since polymers formed by polymerization of diamidediols with triglycolyl chloride are expected to have low softening points, it may not be feasible to use the suspension polymerization method described in U.S. Pat. No. 5,286,837, the teachings of which are incorporated herein. This method fails to yield high molecular weight product if the diamidediol suspension xe2x80x9cmelts downxe2x80x9d due to low oligomer melting point. In this case an alternative method of forming poly(ester-amide)s from diacid chlorides and diamidediols in solution can be utilized (see S. Katayama et al., Journal of Applied Polymer Science, 20, 975-994 (1976), incorporated herein by reference).
An alternative method of forming triglycolic acid poly(ester-amide)s that may be preferable to the use of triglycolyl chloride is to melt polyesterify the diamidediol by reacting it with the dimethyl ester or diethyl ester of triglycolic acid with an appropriate catalyst and with distillation of methanol or ethanol, respectively, as the condensation reaction byproduct. If a slight excess of diamidediol is used, the final reaction conditions of high temperature and low pressure will remove traces of alcohol and any unreacted dimethyl or diethyl triglycolate to give a diol terminated poly(ester-amide). Another method for producing diol terminated poly(ester-amide)s with improved molecular weight is described in U.S. Pat. Nos. 4,209,607 and 4,226,243, the teachings of which are incorporated herein. In this procedure an excess of an aliphatic diol having greater volatility than the diamidediol is added with an appropriate catalyst to an equamolar mixture of diamidediol and diacid diester. As the mixture is heated under conditions of increasing temperature and decreasing pressure, excess aliphatic diol is distilled from the mixture along with the condensation reaction byproduct alcohol to give exceptionally high molecular weight poly(ester-amide) that is diol terminated.
Since it is known that molten glycolide and molten lactide are solvents for poly(ester-amide)s (see U.S. Pat. No. 5,502,092, the teachings of which are incorporated herein), glycolide, lactide, or other cyclic monomers or mixtures of cyclic monomers and the appropriate catalyst (e.g. stannous octoate) can be added to the molten polymer to initiate the polymerization of polyglycolide or polylactide or other polymeric end blocks on the diol terminated poly(ester-amide). This process serves both to increase the polymer molecular weight and to introduce highly crystalline xe2x80x9chard segmentsxe2x80x9d (in the case of glycolide or L-lactide) into the low Tg, soft, rubbery, yet strong and tough, ether containing poly(ester-amide). This type of polymer can be readily freed of unreacted glycolide or lactide, purified, and extruded into monofilament suture by well known methods. Procedures applicable to the synthesis of polyglycolide block copolymers of the present invention are described in U.S. Pat. Nos. 4,429,080; 5,133,739; 5,403,347; and 5,522,841, the teachings of which are incorporated herein.
1,6-Di(hydroxyacetamido)hexane, is a preferred diamidediol because it has been reported to have passed various safety and toxicity tests, is water soluble, yet does not contribute to premature fiber strength loss known to occur with shorter chain diamidediols such as 1,2-di(hydroxyacetamido)ethane.
Bioabsorption of poly(ester-amide)s of the present invention occurs at a reliable rate and is not limited by the choice of the diamidediol since the glycolate ester-like nature of the triglycolate moiety has been discovered in the present invention to be the primary structural feature controlling the rate of polymer hydrolysis. Thus diamidediols formed from ether containing hydroxy acids such as hydroxyethoxy acetic acid, hydroxytetramethyleneoxyacetic acid, and hydroxyhexamethyleneoxyacetic acid can be used to obtain diamidediols that have adequate water solubility and contain ether linkages for improved polymer flexibility. Alternatively, diamidediols also can be formed from hydroxyacids longer than glycolic acid that do not contain ether linkages. An example is 1,6-di(6-hydroxycaproamido)hexane formed by the reaction of 2 moles of caprolactone with 1 mole of hexamethylenediamine (see U.S. Pat. No. 3,025,323, the teachings of which are incorporated herein).
The preparation of hydroxyethoxyacetic acid as a precursor for xcfx81-dioxanone used in the synthesis of poly(dioxanone) has been described in U.S. Pat. No. 4,052,988, the teachings of which are incorporated herein. In this procedure sodium metal is reacted with an excess of ethylene glycol and then chloroacetic acid is added in an amount calculated to be one half the molar quantity of the sodium used. This gives the sodium salt of hydroxyethoxyacetic acid which can be converted into the free acid by precipitation of sodium chloride with HCI. At this point a diamine can be added to produce a xe2x80x9cnylon saltxe2x80x9d precursor of the desired diamidediol which can then be isolated and converted into the diamidediol by heating with distillation of water as described in U.S. Pat. No. 4,529,792, the teachings of which are incorporated herein. In a similar fashion other hydroxyalkyleneoxyacetic acid diamidediols can be obtained with the use of longer chain glycols such as tetramethylene glycol and hexamethylene glycol. In addition, chloroacids with longer methylene chain lengths also can be used in the reaction with glycols to give ether-containing hydroxy acids. For example, 3-chloropropionic acid, 4-chlorobutyric acid, and 5-chlorovaleric acid all can be used in place of chloroacetic acid to produce ether-containing hydroxy acids that are useful in the present invention.
Alternatively, if a stiff bioabsorbable polymer is desired for non-suture applications such as orthopedic fixation pins and rods, a rigid amidediol can be created for example by the reaction of one mole of a diamine with 2 moles of an aromatic hydroxyacid such as 4-hydroxybenzoic acid, 4-hydroxyphenylacetic acid, 4-hydroxyethoxybenzoic acid, 4-(hydroxyethoxy)phenylacetic acid, and the like. A distinct advantage of the present invention is that the chemical structure of the diamidediol is not limited to those structures that contribute to hydrolytic degradability of the polymer since hydrolytic degradability is assured by the presence of triglycolic acid ester linkages. Methods of processing polymers of the present invention into useful forms include melt spinning of fibers, injection molding of parts, and hot pressing or sintering together bundles of fibers or plies of braided, woven, or non-woven fiber layers into self-reinforced composites. Fibers can also be processed into useful structural supports for example as bone fragment fixation devices and inter vertebral discs for spinal fusion by solvent welding. Thus a solution of the polymer can be made in a solvent that does not attack the crystalline regions of the fiber at room temperature. This solution can then be used to glue the fibers together. After evaporation of the solvent by vacuum drying, the composite can be further consolidated and strengthened by hot pressing at a temperature below the crystalline melting temperature of the fiber. This approach also allows for the uniform introduction of drugs or growth factors into the composite by suspending or dissolving the drug or growth factor into the polymer solution used for solvent welding.
An example of a bioabsorbable device made by this technique is a porous, fiber self-reinforced, bone growth factor-releasing implant for accelerated spinal fusion. Such devices are needed to eliminate the pain, morbidity, and expense associated with the use of autologous bone grafts to achieve spinal fusion.
Other methods of processing and utilizing polymers of the present invention will be apparent to those skilled in the art of polymer processing and surgical device fabrication.
The polymers of the present invention have a plurality of units of the general formula:
Hxe2x80x94[xe2x80x94Exe2x80x94]mxe2x80x94Oxe2x80x94Axe2x80x94[xe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94(CH 2)xxe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94Oxe2x80x94Axe2x80x94]pxe2x80x94Oxe2x80x94[xe2x80x94Exe2x80x94]nxe2x80x94H
wherein x is from 2 to 10, m and n are independently from 0 to 2000, p is from 10 to 2000, and A is comprised of from 0 to 90 mole % B in combination with other structures selected from the group consisting of C and
D wherein:
B is defined by the following structure:
xe2x80x94(CH2)xxe2x80x94
wherein x is from 2 to 10; and
C is defined by the following structure:
xe2x80x94R1xe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94R1xe2x80x94
wherein:
a) R1 is selected from the group consisting of
i) linear alkylenes having from 1 to 5 carbon atoms; and
ii) xe2x80x94(CH2)xxe2x80x94Oxe2x80x94(CH2)yxe2x80x94 wherein x (the end attached to the amide carbonyl) is from 1 to 4 and y (the end attached to the ester oxygen) is independently from 2 to 6; and
iii) xe2x80x94(CH2)xxe2x80x94C6H4xe2x80x94 wherein x (the end attached to the amide carbonyl) is from 0 to 1; and
iv) xe2x80x94(CH2)xxe2x80x94C6H4xe2x80x94Oxe2x80x94(CH2)yxe2x80x94 wherein x (the end attached to the amide carbonyl) is from 0 to 1 and y (the end attached to the ester oxygen) is independently from 2 to 6; and
b) R2 is selected from the group consisting of linear alkylenes having from 2 to 10 carbon atoms; and
D is defined by the following structure:
xe2x80x94R3xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94NHxe2x80x94R3xe2x80x94
wherein R3 is a divalent aliphatic or aromatic hydrocarbon radical having from 3 to about 8 carbon atoms; and
E is defined by the following structures:
I. [xe2x80x94COxe2x80x94CHRxe2x80x94Oxe2x80x94] wherein R4 is selected from the group consisting of xe2x80x94H(from glycolide) and xe2x80x94CH3 (from lactide);
II. [-CO-O-(CH2)3xe2x80x94Oxe2x80x94]
III. [xe2x80x94COxe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94]
IV. [xe2x80x94COxe2x80x94(CH2)5xe2x80x94Oxe2x80x94]
and combinations thereof. Note that the above structures I. through IV. are drawn to represent replacement of E on the right side of the general formula and will be reversed for replacement of E on the left side of the general formula.
The preferred embodiments of the present invention are polymers with end blocks (E) of polyglycolide or polylactide wherein R1 is formed from glycolic acid or hydroxycaproic acid (e.g. via caprolactone), and R2 is xe2x80x94(CH2)6xe2x80x94. These polymers have the advantages of excellent initial fiber strength retention in vivo due to resistance of moisture uptake, complete bioabsorption due to amidediol water solubility and the proven bioabsorbability of commercially available glycolic and lactic acid ester containing polymers.